Established estrogen therapies for treatment of hormone-deficiency-induced symptoms and the protective action of estrogens on bones, brains, vessels and other organ systems.
The efficiency of estrogens in the treatment of hormone-deficiency-induced symptoms such as hot flashes, atrophy of estrogen target organs and incontinence, as well as the successful use of estrogen therapies for prevention of bone mass loss in peri- and postmenopausal women, is well documented and generally accepted (Grady et al. 1992, Ann Intern Med 117: 1016–1037). It is also well documented that estrogen replacement therapy in postmenopausal women or in women with ovarian dysfunction that is caused in some other way reduces the risk of cardiovascular diseases compared to non-estrogen-treated women (Grady et al., loc. cit.).
In addition, more recent studies confirm a protective action of estrogens against neurodegenerative diseases, such as, e.g., Alzheimer's disease (Henderson 1997, Neurology 48 (Suppl 7): S27–S35; Birge 1997, Neurology 48 (Suppl 7): S36–S41), a protective action with respect to brain functions, such as memory and learning capacity (McEwen et al. 1997, Neurology 48 (Suppl 7): S8–S15; Sherwin 1997, Neurology 48 (Suppl 7): S21–S26), as well as against hormone-deficiency-induced mood swings (Halbreich 1997, Neurology 48 (Suppl 7): S16–S20).
In addition, estrogen replacement therapy has proven effective relative to the reduction of the incidence of colorectal carcinoma (Calle, E. F. et al., 1995, J Natl Cancer Inst 87: 517–523).
In conventional estrogen or hormone replacement therapy (=HRT), natural estrogens, such as estradiol, and conjugated estrogens that consist of equine urine are used either by themselves or in combination with a gestagen. Instead of the natural estrogens, derivatives that are obtained by esterification, such as, e.g., 17β-estradiol-valerate, can also be used.
Because of the stimulating action of the estrogens that are used on the endometrium, which results in an increase of the risk of endometrial carcinoma (Harlap, S. 1992, Am J Obstet Gynecol 166: 1986–1992), estrogen/gestagen combination preparations are preferably used in hormone replacement therapy. The gestagenic component in the estrogen/gestagen combination avoids hypertrophy of the endometrium, but the occurrence of undesirable intracyclic menstrual bleeding is also linked to the gestagen-containing combination.
Selective estrogens represent a more recent alternative to the estrogen/gestagen combination preparations. Up until now, selective estrogens have been defined as those compounds that have an estrogen-like effect on the brain, bones and vascular system, owing to their antiuterotrophic (i.e., antiestrogenic) partial action, but they do not have a proliferative effect on the endometrium.
A class of substances that partially meet the desired profile of a selective estrogen are the so-called “Selective Estrogen Receptor Modulators” (SERM) (R. F. Kauffman, H. U. Bryant 1995, DNAP 8 (9): 531–539). In this case, there are partial agonists of estrogen receptor subtype “ERα.” This substance type is ineffective, however, with respect to the therapy of acute postmenopausal symptoms, such as, e.g., hot flashes. As an example of a SERM, the raloxifene that was recently introduced for the indication of osteoporosis can be mentioned.
Estrogen Receptor Beta (ERβ)
Estrogen receptor β (ERβ) was recently discovered as a second subtype of the estrogen receptor (Kuiper et al. (1996), Proc. Natl. Acad. Sci. 93: 5925–5930; Mosselman, Dijkema (1996) Febs Letters 392: 49–53; Tremblay et al. (1997), Molecular Endocrinology 11: 353–365). The expression pattern of ERβ differs from that of the ERα (Kuiper et al. (1996), Endocrinology 138: 863–870). ERβ thus predominates over ERα in the rat prostate, while ERα predominates over ERβ in the rat uterus. Areas in which in each case only one of the two ER-subtypes is expressed were identified in the brain (Shugrue et al. (1996), Steroids 61: 678–681; Li et al. (1997), Neuroendocrinology 66:63–67). ERβ is expressed in, i.a., areas that are considered to be important for cognitive processes and “mood” (Shugrue et al. 1997, J Comparative Neurology 388: 507–525).
Other organ systems with comparatively higher ERβ-expression comprise the bones (Onoe, Y. et al., 1997, Endocrinology 138: 4509–4512), the vascular system (Register, T. C., Adams, M. R. 1998, J. Steroid Molec Biol 64: 187–191), the urogenital tract (Kuiper, G. J. M. et al. 1997, Endocrinology 138: 863–870), the gastrointestinal tract (Campbell-Thopson 1997, BBRC 240: 478–483), as well as the testis (Mosselmann, S. et al. 1996 Febs Lett 392 49–53) including the spermatides (Shugrue et al. 1998, Steroids 63: 498–504). The tissue distribution suggests that estrogens regulate organ functions via ERβ. The fact that ERβ is functional in this respect also follows by studies in ERα-(ERKO) or ERβ-(βERKO)-knockout mice: ovariectomy produces bone mass loss in ERKO-mice, which can be cancelled out by estrogen substitution (Kimbro et al. 1998, Abstract OR7-4, Endocrine Society Meeting New Orleans). Estradiol in the blood vessels of female ERKO mice also inhibits vascular media and smooth muscle cell proliferation (Iafrati, M. D. et al. 1997, Nature Medicine 3: 545–548). These protective actions of estradiol are carried out in the ERKO mouse presumably via ERβ.
Observations of βERKO mice provide an indication on a function of ERβ in the prostate and bladder: in the case of older male mice, symptoms of prostate and bladder hyperplasia occur (Krege, J. H. et al. 1998, Proc Natl Acad Sci 95: 15677–15682). In addition, female ERKO mice (Lubahn, D. B. et al. 1993, Proc Natl Acad Sci 90: 11162–11166) and male ERKO mice (Hess, R. A. et al. 1997, Nature 390: 509–512) as well as female βERKO mice (Krege, J. H., 1998) have fertility disorders. Consequently, the important function of estrogens with respect to maintaining testis and ovary functions as well as fertility is confirmed.
Westerlind et al., 1998, describe a differential action of 16α-hydroxyestrone on the bones, on the one hand, and reproductive organs of female rats, on the other (Westerlind et al. 1998, J Bone and Mineral Res 13: 1023–1031).
Some studies showed that 16α-hydroxyestrone binds three times better to the human estrogen receptor β (ERβ) than to the human estrogen receptor a (ERα). The RBA value of the substance on the rat prostate estrogen receptor is five times better than the RBA value of the substance on the rat uterus estrogen receptor. According to some findings, the dissociation of the substance that is described by Westerlind can be attributed to their preference for ERβ rather than ERα.
It was possible to achieve a selective estrogen action on specific target organs by subtype-specific ligands based on the different tissue or organ distribution of the two subtypes of the ERs. Substances with a preference for ERβ compared to ERα in the in vitro receptor binding test were described by Kuiper et al. (Kuiper et al. (1996), Endocrinology 138: 863–870). A selective action of subtype-specific ligands of the estrogen receptor on estrogen-sensitive parameters in vivo was not previously shown.
The object of this invention is therefore to prepare compounds that have in vitro a dissociation with respect to the binding to estrogen receptor preparations from rat prostates and rat uteri and that have in vivo a dissociation with respect to bones rather than the uterus action. The compounds are to have in vitro a higher affinity to estrogen receptor preparations from rat prostates than to estrogen receptor preparations from rat uteri and in vivo a many times higher potency with respect to protection against hormone-deficiency-induced bone mass loss in comparison to uterus-stimulating action.
In the broader sense, a structure-action relationship, which allows for access to compounds that have the above-formulated pharmacological profile of better estrogenic action on bones than on the uterus, is to be made available by this invention.
According to the invention, the object above is achieved by the provision of 16α- and 16β-hydroxy-estra-1,3,5(10)-trienes of general formula I
in which radicals R1 to R17, independently of one another, have the following meanings:                R1 means a halogen atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group, an ethoxy group or a hydrogen atom;        R2 means a halogen atom, a hydroxyl group, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms or a hydrogen atom;        R4 means a halogen atom, a straight-chain or branched-chain, saturated or unsaturated alkyl group with up to 10 carbon atoms, a trifluoromethyl or pentafluoroethyl group, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms or a hydrogen atom;        R7 means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms, an optionally substituted aryl or heteroaryl radical or a hydrogen atom;        R8 means a hydrogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, or a cyano group in α- or position;        R9 means a hydrogen atom in α- or β-position, a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in α- or β-position;        R11 means a nitrooxy group in α- or β-position, a hydroxyl or mercapto group in α- or β-position, a halogen atom in α- or β-position, a chloromethyl group in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with up to 6 carbon atoms, an optionally substituted aryl or heteroaryl radical or a hydrogen atom;        R13 means a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in β-position;        and either        R14 means a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position or a hydrogen atom in α- or β-position and        R15 means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position that can be interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or sulfone groups or imino groups ═NR15′ (R15′=hydrogen atom, methyl, ethyl, propyl, i-propyl) or a hydrogen atom or        R14 and R15 together mean a 14α,15α-methylene or 14β,15β-methylene group that is optionally substituted with one or two halogen atoms;        R16 means a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, a trifluoromethyl or pentafluoroethyl group, a cyanomethyl group or a hydrogen atom in α- or β-position;        R17 means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, a hydrogen atom or a hydroxyl group        and the dotted lines ------ in rings B, C and D optionally mean one or more double bonds, and the wavy lines mean the arrangement of the respective substituent in α- or β-position,for treatment of estrogen-deficiency-induced diseases and conditions.        
According to a variant of the invention, preferably compounds of general formula I are used,
in which radicals R1 to R17, independently of one another, have the following meanings
                R1 means a fluorine atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group, an ethoxy group or a hydrogen atom;        R2 means a fluorine atom, a hydroxyl group, a methoxy or ethoxy group or a hydrogen atom;        R4 means a fluorine atom, a methyl, ethyl, trifluoromethyl, methoxy or ethoxy group or a hydrogen atom;        R7 means a fluorine atom in α- or β-position, a methyl, ethyl, propyl or i-propyl group in α- or β-position, a trifluoromethyl group in α- or β-position or a hydrogen atom;        R8 means a hydrogen atom in α- or β-position, a methyl or ethyl group in α- or β-position;        R9 means a hydrogen atom in α- or β-position, a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in α- or β-position;        R11 means a nitrooxy group in α- or β-position, a hydroxyl group in α- or β-position, a fluorine atom in α- or β-position, a choromethyl group in α- or β-position, a methyl group in α- or β-position, a methoxy group in α- or β-position, a phenyl- or 3-methylthien-2-yl radical in α- or β-position or a hydrogen atom;        R13 means a methyl or ethyl group in β-position; and either        R14 means a hydrogen atom in α- or β-position or a methyl group in α- or β-position and        R15 means a fluorine atom in α- or β-position, a methyl group in α- or β-position, or a hydrogen atom, or        R14 and R15 together mean a 14α,15α-methylene group or a 14β,15β-methylene group;        R16 means a methyl, ethyl, ethinyl, propinyl or trifluoromethyl group;        R17 means a fluorine atom in α- or β-position, a methyl group, a hydrogen atom or a hydroxyl group,        and the dotted lines ----- in rings B, C and D optionally mean an additional double bond between carbon atoms 9 and 11.        
In addition to the above use of the compounds of general formula I, the invention also relates to the compounds of general formula I′ themselves. These are the compounds of general formula I excluding the compounds estra-1,3,5(10)-triene-3,16α-diol, estra-1,3,5(10)-triene-3,16β-diol, estra-1,3,5(10),7-tetraene-3,16α-diol as well as estra-1,3,5(10),7-tetraene-3,16β-diol. These last-mentioned compounds are already known; a selective estrogenic action and its use in the context of this invention has not yet been described, however.
16α-Hydroxy-17-methylene estrogens were described as compounds that have an anti-inflammatory action and that are suitable for the therapy of immunological diseases, especially auto-immune diseases (WO 97/08188).
A differentiated action of 16α-hydroxyestrone was already described by Westerlind et al., see above, but not a different action between the brain functions and the vascular system, on the one hand, and on the uterus, on the other.
3,16α-Dihydroxy-estratriene was already described by Stack and Gorski as “estrogen that has a short-term effect” (Stack, Gorski 1985).
Nothing is known to date on a use of this last-mentioned compound as a selective estrogen.
In the compounds of general formulas I and I′ as well as in partial structures II and II′ that are described below, a fluorine, chlorine, bromine or iodine atom can always stand for a halogen atom; a fluorine atom is preferred in each case.
The alkoxy groups in the compounds of general formulas I and I′ as well as in partial structures II and II′ that are described below can contain 1 to 6 carbon atoms in each case, whereby methoxy, ethoxy, propoxy, isopropoxy and t-butyloxy groups are preferred.
As representatives of the alkylthio groups, for example, methylthio, ethylthio and trifluoromethylthio groups can be mentioned.
Within the context of this invention, an aryl radical is a phenyl, 1- or 2-naphthyl radical; the phenyl radical is preferred.
Unless expressly indicated, aryl always also includes a heteroaryl radical. Examples of a heteroaryl radical are the 2-, 3- or 4-pyridinyl, the 2- or 3-furyl, the 2- or 3-thienyl, the 2-or 3-pyrrolyl, the 2-, 4- or 5-imidazolyl, the pyrazinyl, the 2-, 4- or 5-pyrimidinyl or 3- or 4-pyridazinyl radical.
As substituents for an aryl or heteroaryl radical, for example, a methyl-, ethyl-, trifluoromethyl-, pentafluoroethyl-, trifluoromethylthio-, methoxy-, ethoxy-, nitro-, cyano-, halogen- (fluorine, chlorine, bromine, iodine), hydroxy-, amino-, mono(C1-8 alkyl) or di(C1-8 alkyl)amino, whereby both alkyl groups are identical or different, di(aralkyl)amino, whereby both aralkyl groups are identical or different, can be mentioned.
As representatives of straight-chain or branched-chain alkyl groups with 1–10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl, decyl can be mentioned; methyl, ethyl, propyl and isopropyl are preferred.
The alkyl groups can be partially or completely fluorinated or substituted by 1–5 halogen atoms, hydroxy groups or C1–C4 alkoxy groups.
As perfluorinated alkyl groups, for example, trifluoromethyl, pentafluoroethyl and nonafluorobutyl can be mentioned. Representatives of partially fluorinated alkyl groups are, for example, 2,2,2-trifluoroethyl, 5,5,5,4,4-pentafluoropentyl, 9,9,9,8,8,7,7,6,6-nonafluorohexyl, etc.
Monochloromethylene, monofluoromethylene or difluoromethylene can stand for the halogen-substituted 14,15-methylene group.
Other variants of the invention provide one or more conjugated double bonds in rings B, C and D of the estratriene skeleton:
A double bond between C atoms 6 and 7 or between C atoms 7 and 8 or between C atoms 8 and 9 or between C atoms 9 and 11 or between C atoms 8 and 14 or between C atoms 14 and 15 or double bonds between C atoms 6 and 7 and C atoms 8 and 9 or between C atoms 8 and 9 and C atoms 14 and 15 or between C atoms 6 and 7, C atoms 8 and 9 and C atoms 11 and 12 or between C atoms 6 and 7, C atoms 8 and 9 and C atoms 14 and 15 or between C atoms 6 and 7, C atoms 8 and 9, C atoms 11 and 12 and C atoms 14 and 15.
One or both hydroxyl groups at C atoms 3 and 16 can be esterified with an aliphatic, straight-chain or branched-chain, saturated or unsaturated C1–C14 mono- or polycarboxylic acid or an aromatic carboxylic acid or with an α- or β-amino acid.
Suitable as such carboxylic acids for esterification are, for example:
Monocarboxylic acids: formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, pivalic acid, lauric acid, myristic acid, acrylic acid, propiolic acid, methacrylic acid, crotonic acid, isocrotonic acid, oleic acid, elaidic acid.
Dicarboxylic acids: oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, maleic acid, fumaric acid, muconic acid, citraconic acid, and mesaconic acid.
Aromatic carboxylic acids: benzoic acid, phthalic acid, isophthalic acid, terephthalic acid, naphthoic acid, o-, m- and p-toluic acid, hydratropic acid, atropic acid, cinnamic acid, nicotinic acid, and isonicotinic acid.
As amino acids, the representatives of these classes of substances that are known sufficiently to one skilled in the art are suitable, for example, alanine, β-alanine, arginine, cysteine, cystine, glycine, histidine, leucine, isoleucine, phenylalanine, proline, etc.
The 16-oxy group in the compounds according to the invention and the structural parts that are described below can be both in α-position and in β-position.
A variant of the invention provides that in compounds of general formulas I and I′ as well as in the structural parts of formula II′                R7 means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms and/or an optionally substituted aryl or heteroaryl radical and        
R1, R2, R4, R8, R9, R11, R14, R15, R16 and R17 in each case mean a hydrogen atom.
According to another embodiment of the invention, in the compounds of general formulas I and I′, and in the structural parts of formula II′                R11 means a nitrooxy group in α- or β-position, a hydroxyl or mercapto group in α- or β-position, a halogen atom in α- or β-position, a chloromethyl group in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with up to 6 carbon atoms or an optionally substituted aryl or heteroaryl radical, and        R1, R2, R4, R7, R8, R9, R14, R15, R16 and R17 in each case mean a hydrogen atom.        
Another configuration of the compounds of general formulas I and I′ as well as the structural parts of formula II′ provides that                R15 means a halogen atom in α- or β-position or a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position that can be interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or sulfone groups or imino groups ═NR15′ (R15′=hydrogen atom, methyl, ethyl, propyl, i-propyl), and        R1, R2, R4, R7, R8, R9, R11, R14, R16 and R17 in each case mean a hydrogen atom.        
In another variant of the compounds of general formulas I and I′ according to the invention as well as the structural parts of formula II′,                R7 means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms or an optionally substituted aryl or heteroaryl radical, and        R11 means a nitrooxy group in α- or β-position, a hydroxyl- or mercapto group in α- or β-position, a halogen atom in α- or β-position, a chloromethyl group in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with up to 6 carbon atoms or an optionally substituted aryl or heteroaryl radical, and        R1, R2, R4, R8, R9, R14, R15, R16 and R17 in each case mean a hydrogen atom.        
In another variant of the compounds of general formulas I and I′ according to the invention as well as the structural parts of formula II′,                R7 stands for a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms or an optionally substituted aryl or heteroaryl radical, and        R15 stands for a halogen atom in α- or β-position or a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position that can be interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or sulfone groups or imino groups ═NR15′ (R15′=hydrogen atom, methyl, ethyl, propyl, i-propyl), and        R1R2, R4, R8, R9, R11, R14, R16 and R17 in each case stand for a hydrogen atom.        
According to another embodiment of the compounds of general formulas I and I′ according to the invention and the structural parts of formula II′,                R11 stands for a nitrooxy group in α- or β-position, a hydroxyl or mercapto group in α- or β-position, a halogen atom in α- or β-position, a chloromethyl group in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with up to 6 carbon atoms or an optionally substituted aryl or heteroaryl radical, and        R15 stands for a halogen atom in α- or β-position or a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position that can be interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or sulfone groups or imino groups ═NR15 (R15=hydrogen atom, methyl, ethyl, propyl, i-propyl), and        R1, R2, R4, R7, R8, R9, R14, R16, and R17 in each case stand for a hydrogen atom.        
There are also embodiments of the compounds of general formulas I and I′ according to the invention as well as the structural parts of formula II′, in which                R7 means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms or an optionally substituted aryl or heteroaryl radical,        R11 means a nitrooxy group in α- or β-position, a hydroxyl or mercapto group in α- or β-position, a halogen atom in α- or β-position, a chloromethyl group in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with up to 6 carbon atoms or an optionally substituted aryl or heteroaryl radical,        R15 means a halogen atom in α- or β-position, or a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position that can be interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or sulfone groups or imino groups ═NR15′ (R15′=hydrogen atom, methyl, ethyl, propyl, i-propyl), and        R1, R2, R4, R8, R9, R14, R16, and R17 in each case mean a hydrogen atom.        
In the variants of the compounds of general formula I according to the invention that are indicated above as well as the partial structures of general formula II′,                R7 preferably stands for a fluorine atom in α- or β-position, a methyl, ethyl, propyl or i-propyl group in α- or β-position, a trifluoromethyl group in α- or β-position or a hydrogen atom;        R11 preferably stands for a nitrooxy group in α- or position, a hydroxyl group in α- or β-position, a fluorine atom in α- or β-position, a chloromethyl group in α- or β-position, a methyl group in α- or β-position, a methoxy group in α- or β-position, a phenyl or 3-methylthien-2-yl radical in α- or position or a hydrogen atom and        R15 preferably stands for a fluorine atom in α- or position, a methyl group in α- or β-position or a hydrogen atom.        
Preferred according to this invention are the compounds below:    14α,15α-Methylen-estra-1,3,5(10)-triene-3,16α-diol    14β,15β-Methylen-estra-1,3,5(10)-triene-3,16α-diol    14β,15β-Methylen-estra-1,3,5(10),8(9)-tetraene-3,16α-diol,    Estra-1,3,5(10),8(9)-tetraene-3,16α-diol,    Estra-1,3,5(10),8(14)-tetraene-3,16α-diol,    Estra-1,3,5(10),6,8-pentaene-3,16α-diol,    7α-Fluoro-estra-1,3,5(10)-triene-3,16α-diol,    11-Methoxy-estra-1,3,5(10)-triene-3,16α-diol,    7α-Methyl-estra-1,3,5(10)-triene-3,16α-diol    11′-Fluoro-estra-1,3,5(10)-triene-3,16α-diol,    8α-Estra-1,3,5(10)-triene-3,16α-diol    Estra-1,3,5(10)-triene-2,3,16α-triol    17β-Fluoro-estra-1,3,5(10)-triene-3,16α-diol,    18α-Homo-estra-1,3,5(10)-triene-3,16α-diol,    18α-Homo-estra-1,3,5(10),8(9)-tetraene-3,16α-diol,    18α-Homo-14α,15α-methylen-estra-1,3,5(10)-triene-3,16α-diol,    18α-Homo-14α,15α-methylen-estra-1,3,5(10),8(9)-tetraene-3,16α-diol,    18α-Homo-14α,15α-methylen-estra-1,3,5(10),6,8-pentaene-3,16α-diol.    14α,15α-Methylen-estra-1,3,5(10)-triene-3,16β-diol    14β,15β-Methylen-estra-1,3,5(10)-triene-3,16β-diol    14β,15β-Methylen-estra-1,3,5(10),8(9)-tetraene-3,16β-diol,    Estra-1,3,5(10),8(9)-tetraene-3,16β-diol,    Estra-1,3,5(10),8(14)-tetraene-3,16β-diol,    Estra-1,3,5(10),6,8-pentaene-3,16β-diol,    7α-Fluoro-estra-1,3,5(10)-triene-3,16β-diol,    11β-Methoxy-estra-1,3,5(10)-triene-3,16β-diol,    7α-Methyl-estra-1,3,5(10)-triene-3,16β-diol    11β-Fluoro-estra-1,3,5(10)-triene-3,16β-diol,    8α-Estra-1,3,5(10)-triene-3,16β-diol    Estra-1,3,5(10)-triene-2,3,16α-triol    17β-Fluoro-estra-1,3,5(10)-triene-3,16β-diol,    18α-Homo-estra-1,3,5(10)-triene-3,16β-diol,    18α-Homo-estra-1,3,5(10),8(9)-tetraene-3,16β-diol,    18α-Homo-14α,15α-methylen-estra-1,3,5(10)-triene-3,16β-diol,    18α-Homo-14α,15α-methylen-estra-1,3,5(10),8(9)-tetraene-3,16β-diol,    18α-Homo-14α,15α-methylen-estra-1,3,5(10),6,8-pentaene-3,16β-diol,    7α-Ethyl-estra-1,3,5(10)-triene-3,16α-diol    7α-Propyl-estra-1,3,5(10)-triene-3,16α-diol    7α-i-Propyl-estra-1,3,5(10)-triene-3,16α-diol    7α-i-Propenyl-estra-1,3,5(10)-triene-3,16α-diol    7α-Phenyl-estra-1,3,5(10)-triene-3,16α-diol    7α-Methoxy-estra-1,3,5(10)-triene-3,16α-diol    7α-Thiomethyl-estra-1,3,5(10)-triene-3,16α-diol    7β-Cyanomethyl-estra-1,3,5(10)-triene-3,16β-diol    7β-Ethyl-estra-1,3,5(10)-triene-3,16≢-diol    7β-Propyl-estra-1,3,5(10)-triene-3,16α-diol    7β-i-Propyl-estra-1,3,5(10)-triene-3,16α-diol    7β-i-Propenyl-estra-1,3,5(10)-triene-3,16α-diol    7β-Phenyl-estra-1,3,5(10)-triene-3,16α-diol    7β-Methoxy-estra-1,3,5 (10)-triene-3,16α-diol    7β-Thiomethyl-estra-1,3,5(10)-triene-3,16α-diol    7β-Cyanomethyl-estra-1,3,5(10)-triene-3,16α-diol    7α-Ethyl-estra-1,3,5(10)-triene-3,16β-diol    7α-Propyl-estra-1,3,5(10)-triene-3,16β-diol    7α-i-Propyl-estra-1,3,5(10)-triene-3,16β-diol    7α-i-Propenyl-estra-1,3,5(10)-triene-3,16β-diol    7α-Phenyl-estra-1,3,5(10)-triene-3,16β-diol    7α-Methoxy-estra-1,3,5(10)-triene-3,16β-diol    7α-Thiomethyl-estra-1,3,5(10)-triene-3,16β-diol    7α-Cyanomethyl-estra-1,3,5(10)-triene-3,16β-diol    7β-Ethyl-estra-1,3,5(10)-triene-3,16β-diol    7β-Propyl-estra-1,3,5(10)-triene-3,16β-diol    7β-i-Propyl-estra-1,3,5(10)-triene-3,16β-diol    7β-i-Propenyl-estra-1,3,5(10)-triene-3,16β-diol    7β-Phenyl-estra-1,3,5(10)-triene-3,16β-diol    7β-Methoxy-estra-1,3,5(10)-triene-3,16β-diol    7β-Thiomethyl-estra-1,3,5(10)-triene-3,16β-diol    7β-Cyanomethyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Methyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Ethyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Propyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Allyl-estra-1,3,5(10)-triene-3,16α-diol    15α-i-Propyl-estra-1,3,5(10)-triene-3,16α-diol    15α-i-Propenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Methoxy-estra-1,3,5(10)-triene-3,16α-diol    15α-Thiomethyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Methyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Ethyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Propyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Allyl-estra-1,3,5(10)-triene-3,16β-diol    15α-i-Propyl-estra-1,3,5(10)-triene-3,16β-diol    15α-i-Propenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Methoxy-estra-1,3,5(10)-triene-3,16β-diol    15α-Thiomethyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Methyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Ethyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Propyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Allyl-estra-1,3,5(10)-triene-3,16α-diol    15β-i-Propyl-estra-1,3,5(10)-triene-3,16α-diol    15β-i-Propenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Methoxy-estra-1,3,5(10)-triene-3,16α-diol    15β-Thiomethyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Methyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Ethyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Propyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Allyl-estra-1,3,5(10)-triene-3,16β-diol    15β-i-Propyl-estra-1,3,5(10)-triene-3,16β-diol    15β-i-Propenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Methoxy-estra-1,3,5(10)-triene-3,16β-diol    15β-Thiomethyl-estra-1,3,5(10)-triene-3,16β-diol    7α-Trifluoromethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7α-Pentafluoroethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7α-Ethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7α-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7α-i-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7α-i-Propenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7α-Phenyl-11α-Fluoro-estra-1,3,5(10)-triene-3,16α-diol    7α-Methoxy-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7α-Thiomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7α-Cyanomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7β-Ethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7β-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7β-i-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7β-i-Propenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7β-Phenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7β-Methoxy-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7β-Thiomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7α-Cyanomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    7α-Ethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7α-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7α-i-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7α-i-Propenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7α-Phenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7α-Methoxy-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7α-Thiomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7α-Cyanomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7β-Ethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7β-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7β-i-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7β-i-Propenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7β-Phenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7β-Methoxy-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7β-Thiomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    7β-Cyanomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15α-Methyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15α-Ethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15α-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15α-Allyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15α-i-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15α-i-Propenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15α-Methoxy-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15α-Thiomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15α-Methyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15α-Ethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15α-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15α-Allyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15α-i-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15α-i-Propenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15α-Methoxy-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15α-Thiomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15β-Methyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15β-Ethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15β-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15β-Allyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15β-i-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15β-i-Propenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15β-Methoxy-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15β-Thiomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16α-diol    15β-Methyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15β-Ethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15β-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15β-Allyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15β-i-Propyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15β-i-Propenyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15β-Methoxy-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    15β-Thiomethyl-11β-fluoro-estra-1,3,5(10)-triene-3,16β-diol    14α,15α-Methylene-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    14β,15β-Methylene-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    14β,15β-Methylene-7α-phenyl-estra-1,3,5(10),8(9)-tetraene-3,16α-diol,    7α-Phenyl-estra-1,3,5(10),8(9)-tetraene-3,16α-diol,    7α-Phenyl-estra-1,3,5(10),8(14)-tetraene-3,16α-diol,    7α-Phenyl-estra-1,3,5(10),6,8-pentaene-3,16α-diol,    11β-Methoxy-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,    11β-Fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,    7α-Phenyl-8α-estra-1,3,5(10)-triene-3,16α-diol    7α-Phenyl-estra-1,3,5(10)-triene-2,3,16α-triol    17β-Fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,    18α-Homo-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,    18α-Homo-7α-phenyl-estra-1,3,5(10),8(9)-tetraene-3,16α-diol,    18α-Homo-14α,15α-methylene-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,    18α-Homo-14α,15α-methylene-7α-phenyl-estra-1,3,5(10),8(9)-tetraene-3,16α-diol,    18α-Homo-14α,15α-methylene-7α-phenyl-estra-1,3,5(10),6,8-pentaene-3,16α-diol,    14α,15α-Methylene-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    14β,15β-Methylene-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    14β,15β-Methylene-7α-phenyl-estra-1,3,5(10),8(9)-tetraene-3,16β-diol,    7α-Phenyl-estra-1,3,5(10),8(9)-tetraene-3,16β-diol,    7α-Phenyl-estra-1,3,5(10),8(14)-tetraene-3,16β-diol,    7α-Phenyl-estra-1,3,5(10),6,8-pentaene-3,16β-diol,    11β-Methoxy-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol,    11β-Fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,    7α-Phenyl-8α-estra-1,3,5(10)-triene-3,16β-diol    7α-Phenyl-estra-1,3,5(10)-triene-2,3,16α-triol    17β-Fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,    18α-Homo-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol,    18α-Homo-7α-phenyl-estra-1,3,5(10),8(9)-tetraene-3,16β-diol,    18α-Homo-14α,15α-methylene-7α-phenyl-estra-1,3,5(10)-triene-3,16%-diol,    18α-Homo-14α,15α-methylene-7α-phenyl-estra-1,3,5(10),8(9)-tetraene-3,16β-diol,    18α-Homo-14α,15α-methylene-7α-phenyl-estra-1,3,5(10),6,8-pentaene-3,16β-diol,    15α-Methyl-7α-phenyl-estra-1,3,5(10)-triene-3,16-diol    15α-Ethyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Propyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Allyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-i-Propyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-i-Propenyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Methoxy-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Thiomethyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Methyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Ethyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Propyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Allyl-7 μL-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-i-Propyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-i-Propenyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Methoxy-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Thiomethyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Methyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Ethyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Propyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Allyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-i-Propyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-i-Propenyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Methoxy-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Thiomethyl-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15′-Methyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Ethyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Propyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Allyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-i-Propyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-i-Propenyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Methoxy-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Thiomethyl-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Methyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Ethyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Propyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Allyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-i-Propyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-i-Propenyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Methoxy-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Thiomethyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15α-Methyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Ethyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Propyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Allyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-i-Propyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-i-Propenyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Methoxy-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15α-Thiomethyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Methyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Ethyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Propyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Allyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-i-Propyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-i-Propenyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Methoxy-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Thiomethyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16α-diol    15β-Methyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Ethyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Propyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Allyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-i-Propyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-i-Propenyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Methoxy-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    15β-Thiomethyl-11β-fluoro-7α-phenyl-estra-1,3,5(10)-triene-3,16β-diol    11β-[2-(3-Methylthien)-yl)-estra-1,3,5(10)-triene-3,16α-diol    11β-[2-(3-Methylthien)-yl)-estra-1,3,5(10)-triene-3,16β-dioland of the latter in turn especially the compounds    7α-Fluoro-estra-1,3,5(10)-triene-3,16α-diol,    7α-Methyl-estra-1,3,5(10)-triene-3,16β-diol    7α-Methyl-estra-1,3,5(10)-triene-3,16α-diol    18α-Homo-estra-1,3,5(10)-triene-3,16α-diol.
Another aspect of this invention relates to the use of the structural part of formula II
as a component of the total structure of compounds that have a dissociation in favor of their estrogenic action on bone rather than the uterus.
The possible substituents in carbon atoms 7, 8, 9, 11, 13, 14, 15 and 17 can be respectively in α- or β-position. The dotted lines ----- in rings B, C and D stand for one or more possible double bonds between the corresponding carbon atoms.
This invention preferably relates to those structural parts of general formula II′
in which radicals R1′ to R17′, independently of one another, have the following meanings                R1′ means a halogen atom, a hydroxyl group, a methyl group, a trifluoromethyl group, a methoxy group, an ethoxy group or a hydrogen atom;        R2′ means a halogen atom, a hydroxyl group, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms or a hydrogen atom;        R4′ means a halogen atom, a straight-chain or branched-chain, saturated or unsaturated alkyl group with up to 10 carbon atoms, a trifluoromethyl or pentafluoroethyl group, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms or a hydrogen atom;        R7′ means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy group with up to 6 carbon atoms, an optionally substituted aryl or heteroaryl radical or a hydrogen atom;        R8′ means a hydrogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position or a cyano group in α- or β-position;        R9′ means a hydrogen atom in α- or β-position, a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in α- or β-position;        R11′ means a nitrooxy group in α- or β-position, a hydroxyl or mercapto group in α- or β-position, a halogen atom in α- or β-position, a chloromethyl group in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated alkoxy or alkylthio group with up to 6 carbon atoms, an optionally substituted aryl or heteroaryl radical or a hydrogen atom;        R13′ means a methyl, ethyl, trifluoromethyl or pentafluoroethyl group in β-position;        and either        R14′ means a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position or a hydrogen atom in α- or position and        R15′ means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position that can be interrupted by one or more oxygen atoms, sulfur atoms, sulfoxide or sulfone groups or imino groups ═NR15 (R15′=hydrogen atom, methyl, ethyl, propyl, i-propyl) or a hydrogen atom or        R14′ and R15′ together mean a 14α,15α-methylene group or a 14β,15β-methylene group that is optionally substituted with one or two halogen atoms;        R16′ means a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, a trifluoromethyl or pentafluoroethyl group, a cyanomethyl group or a hydrogen atom in α- or β-position;        R17′ means a halogen atom in α- or β-position, a straight-chain or branched-chain, saturated or unsaturated, optionally partially or completely fluorinated alkyl group with up to 10 carbon atoms in α- or β-position, a hydrogen atom or a hydroxyl group,        
and the dotted lines ---- in rings B, C and D optionally mean one or more double bonds, and the wavy lines mean the arrangement of the respective substituent in α- or β-position.
In this patent application, novel structures for selective estrogens are described, which have in vitro dissociation with respect to binding to estrogen receptor preparations of rat prostates and rat uteri and which have in vivo dissociation with respect to bone action rather than uterus action: the substances act in a bone-protective manner over a wide dose range without stimulating the uterus. In the same dose range, their liver action is small. In addition, the substances exert estrogen-like action on the vascular system and brain functions.
The invention also relates to pharmaceutical preparations that contain at least one compound of general formula I (or physiologically compatible addition salts with organic and inorganic acids of them) and the use of these compounds for the production of pharmaceutical agents, especially for the indications below.
The compounds can be used for the following indications both after oral and parenteral administration.
The novel selective estrogens that are described in this patent can be used as individual components in pharmaceutical preparations or in combination especially with antiestrogens or gestagens. Especially preferred is the combination of selective estrogens with ERα-selective antiestrogens, or with antiestrogens that are peripherally-selectively active, i.e., that do not pass through the blood-brain barriers.
The substances and the pharmaceutical agents that contain them are especially suitable for the treatment of peri- and postmenopausal symptoms, especially hot flashes, sleep disturbances, irritability, mood swings, incontinence, vaginal atrophy, and hormone-deficiency-induced emotional diseases. The substances for hormone substitution and therapy of hormone-deficiency-induced symptoms in the case of surgical, medicinal or ovarian dysfunction that is caused in some other way are also suitable. Prevention of bone mass loss in postmenopausal women, in women who have undergone hysterectomies or in women who were treated with LHRH agonists or LHRH antagonists is also part of this.
The compounds are also suitable for alleviating symptoms of male menopause and female menopause, i.e., for male and female hormone replacement therapy (HRT), specifically both for prevention and for treatment, in addition for treatment of symptoms that are accompanied by a dysmenorrhea as well as for treatment of acne.
In addition, the substances can be used for prophylaxis against hormone-deficiency-induced bone mass loss and osteoporosis, for prevention of cardiovascular diseases, especially vascular diseases such as arteriosclerosis, for prevention of the proliferation of arterial smooth muscle cells, for treatment of primary pulmonary high blood pressure and for prevention of hormone-deficiency-induced neurodegenerative diseases, such as Alzheimer's disease, as well as hormone-deficiency-induced impairment of memory and learning capacity.
In addition, the substances can be used for treatment of inflammatory diseases and diseases of the immune system, especially auto-immune diseases, such as, e.g., rheumatoid arthritis.
In addition, the compounds can be used for the treatment of male fertility disorders and prostatic diseases.
The compounds can also be used in combination with the natural vitamin D3 or with calcitriol analogues for bone formation or as supporting therapies to therapies that cause bone mass loss (for example, therapy with glucocorticoids, chemotherapy).
Finally, the compounds of general formula I can be used in connection with progesterone receptor antagonists, specifically especially for use in hormone replacement therapy and for treatment of gynecological disorders.
A therapeutic product that contains an estrogen and a pure antiestrogen for simultaneous, sequential or separate use for the selective estrogen therapy of perimenopausal or postmenopausal conditions is already described in EP-A 0 346 014.
The amount of a compound of general formula I that is to be administered varies within a wide range and can cover any effective amount. On the basis of the condition that is to be treated and the type of administration, the amount of the compound that is administered can be 0.01 μg/kg–10 mg/kg of body weight, preferably 0.04 μg/kg–1 mg/kg of body weight, per day.
In humans, this corresponds to a dose of 0.8 μg to 800 mg, preferably 3.2 μg to 80 mg, daily.
According to the invention, a dosage unit contains 1.6 μg to 200 mg of one or more compounds of general formula I.
The compounds according to the invention and the acid addition salts are suitable for the production of pharmaceutical compositions and preparations. The pharmaceutical compositions or pharmaceutical agents contain as active ingredient one or more of the compounds according to the invention or their acid addition salts, optionally mixed with other pharmacologically or pharmaceutically active substances. The production of the pharmaceutical agents is carried out in a known way, whereby the known and commonly used pharmaceutical adjuvants as well as other commonly used vehicles and diluents can be used.
As such vehicles and adjuvants, for example, those are suitable that are recommended or indicated in the following bibliographic references as adjuvants for pharmaceutics, cosmetics and related fields: Ullmans Encyklopädie der technischen Chemie [Ullman's Encyclopedia of Technical Chemistry], Volume 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), page 918 ff., issued by Czetsch-Lindenwald, Hilfsstoffe für Pharmazie und angrenzende Gebiete [Adjuvants for Pharmaceutics and Related Fields]; Pharm. Ind., Issue 2, 1961, p. 72 and ff.: Dr. H. P. Fiedler, Lexikon der Hilfsstoffe für Pharmazie, Kosmetik und angrenzende Gebiete [Dictionary of Adjuvants for Pharmaceutics, Cosmetics and Related Fields], Cantor KG, Aulendorf in Wurttemberg 1971.
The compounds can be administered orally or parenterally, for example intraperitoneally, intramuscularly, subcutaneously or percutaneously. The compounds can also be implanted in the tissue.
For oral administration, capsules, pills, tablets, coated tablets, etc., are suitable. In addition to the active ingredient, the dosage units can contain a pharmaceutically compatible vehicle, such as, for example, starch, sugar, sorbitol, gelatin, lubricant, silicic acid, talc, etc.
For parenteral administration, the active ingredients can be dissolved or suspended in a physiologically compatible diluent. As diluents, very often oils with or without the addition of a solubilizer, a surfactant, a suspending agent or an emulsifying agent are used. Examples of oils that are used are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.
The compounds can also be used in the form of a depot injection or an implant preparation, which can be formulated so that a delayed release of active ingredient is made possible.
As inert materials, implants can contain, for example, biodegradable polymers, or synthetic silicones such as, for example, silicone rubber. In addition, for percutaneous administration, the active ingredients can be added to, for example, a patch.
For the production of intravaginal systems (e.g., vaginal rings) or intrauterine systems (e.g., pessaries, coils, IUDs, Mirena®) that are loaded with active compounds of general formula I for local administration, various polymers are suitable, such as, for example, silicone polymers, ethylene vinyl acetate, polyethylene or polypropylene.
To achieve better bio-availability of the active ingredient, the compounds can also be formulated as cyclodextrin clathrates. For this purpose, the compounds are reacted with α-, β-, or γ-cyclodextrin or derivatives of the latter (PCT/EP95/02656).
According to the invention, the compounds of general formula I can also be encapsulated with liposomes.
Methodology
Estrogen Receptor Binding Studies
The binding affinity of the new selective estrogens was tested in competitive experiments with use of 3H-estradiol as a ligand to estrogen receptor preparations of rat prostates and rat uteri. The preparation of prostate cytosol and the estrogen receptor test with prostate cytosol was carried out as described by Testas et al. (1981) (Testas, J. et al., 1981, Endocrinology 109: 1287–1289).
The preparation of rat uterus cytosol, as well as the receptor test with the ER-containing cytosol were basically performed as described by Stack and Gorski, 1985 (Stack, Gorski 1985, Endocrinology 117, 2024–2032) with some modification as described in Fuhrmann et al. (1995) (Fuhrmann, U. et al. 1995, Contraception 51: 45–52).
The substances that are described in this patent have higher binding affinity to the estrogen receptor of rat prostates than to estrogen receptors of rat uteri. In this case, it is assumed that ERβ predominates in the rat prostates over ERα, and ERα predominates in rat uteri over ERβ. Table 1 shows that the ratio of the binding to prostate and uterus receptors qualitatively coincides with the quotient of relative binding affinity (RBA) to human ERβ and ERα of rats (according to Kuiper et al. (1996), Endocrinology 138: 863–870) (Table 1).
Some studies with human estrogen receptors α and β, which were produced by means of the Baculovirus/SF-9 expression system, confirm the agreement of the ‘RBA prostate-ER/RBA uterus-ER’ ratio with the ‘RBA ERβ/RBA ERα’ quotient (Table 2).
In addition, the predictability of the ‘prostate-ER versus the uterus-ER test system’ was confirmed with respect to tissue-selective action by in vivo studies. Substances with a preference for prostate-ER are dissociated in vivo with respect to bone and uterus action in favor of action on bones.
Bone Studies
Three-month-old female rats are ovariectomized and treated once daily with the test compound immediately after the operation for 28 days. The administration is carried out subcutaneously in arachis oil/ethanol. The animals are sacrificed on the day after the last administration, and tibia as well as uteri are removed. The uteri are weighed, fixed and worked up for histological studies. The determination of bone density is carried out ex vivo on prepared long bones by means of pQCT (quantitative computer tomography). The measurements are made at a distance of 4–6 mm from the ball of the joint of the proximal tibia.
The ovariectomy reduces the density of the trabecular bone in the measured area by about 400 mg of Ca2+/cm3 to about 300 mg of Ca2+/cm3. By treatment with a compound of general formula I according to this invention, the degradation of the bone density is prevented or inhibited. The bone density in the proximal tibia was measured.
Table 3 shows the results for the compound estra-1,3,5(10)-triene-3,16α-diol that is to be used according to the invention. In accordance with the higher binding affinity to ERβ than to ERα, [ERα (RBA)/ERα (RBA) 6] shows a higher binding affinity to the estrogen receptor of rat prostates [ER(RBA)=50] than to the estrogen receptor of rat uteri [ER(RBA)=9]. Estra-1,3,5(10)-triene-3,16α-diol reflects this in vivo in the greatly different amounts, which produce a 50% bone protection [3 μg/animal] or a 50% uterus stimulation [30 μg/animal], relative to the bone mass loss, which can be measured in ovariectomized, untreated female rats 28 days after the ovariectomy unlike in intact animals that are subjected to sham operations.
The vascular action of the estrogens according to the invention is determined in the model of the ApoE-knockout mouse, as described by R. Elhage et al., 1997, (Elhage, R. et al. 1997, Arteriosclerosis, Thrombosis and Vascular Biology 17: 2679–2684).
To detect the action of estrogens in the brain function, the oxytocin receptor mRNA expression is used as a surrogate parameter (Hrabovszky, E. et al. 1998, Endocrinology 1339: 2600–2604). Ovariectomized rats are treated for 7 days with the test substance or vehicle (administration: subcutaneous or oral, six times daily). On day 7 after the first administration, the animals are decapitated, the uterus weight is determined, and the oxytocin receptor mRNA level is studied by means of in situ hybridization in suitable brain sections. The ED50 values are determined with respect to stimulation of uterus growth and induction of the oxytocin receptor mRNA.
Production of the Compounds According to the Invention
For the production of the compounds according to the invention, i.e., modified/substituted derivatives of estra-1,3,5(10)-triene-3,16ξ-diols, mainly two generally applicable synthesis strategies are used.
On the one hand, especially 3,16-protected derivatives of estra-1,3,5(10)-triene-3,16ξ-diols can be used, however, optionally also the free diols can be used for modifications to individual positions of the skeleton.
The synthesis of 11-nitrate esters represents a typical example. The known diacetate of estra-1,3,5(10)-triene-3,16β-diol (J. Biol. Chem. 1955, 213, 343), which first is oxidized in C(9) and C(11)-positions according to a method by Sykes et al. (Tetrahedron Letters 1971, 3393), forms the starting point. The reductive removal of the benzylic C(9)-hydroxyl group already yields the 11-nitrate ester of estra-1,3,5(10)-triene-3,11β,16β-triol that is protected as a diacetate. After saponification, the epimeric 11-nitrate ester of estra-1,3,5(10)-triene-3,16α-diol then results from an inversion of the C(16)-hydroxyl group. The synthesis diagram that is outlined above can also run in reverse, if the diacetate of the estra-1,3,5(10)-triene-3,16α-diol is selected as a starting point. In this way, the 11-nitrate ester in the 16α-hydroxy series is produced first. Other compounds that result from intermediate products, such as, e.g., 11-nitrate esters of estra-1,3,5(10)-triene-3,9,11β-16ξ-tetraole are also obtained after cleavage of protective groups at C(3), C(16).
On the other hand, corresponding modified estrone analogs, which can be obtained in large numbers in known methods (characteristic but not limiting synthesis processes, which are useful for provision of representative substation patterns in the estrone skeleton, also in combination in several substituents, are found in, for example, C(1) J. Chem. Soc. (C) 1968, 2915; C(7) Steroids 54, 1989, 71; C(8α) Tetrahedron Letters 1991, 743; C(8β) Tetrahedron Letters 1964, 1763; Tetrahedron 1969, 25, 4011; J. Org. Chem. 1970, 35, 468; C(11) J. Steroid Biochem. 31, 1988, 549; C(9) J. Chem. Soc. Perk. 1 1973, 2095; C(15) J. Chem. Soc. Perk. 1 1996, 1269), offer flexible access to the compounds according to the invention by transposition of the oxygen functionality (Z. Chem. 1970, 221) of C(17) to C(16). Such novel derivatives of estrone are also suitable for this purpose, however.
For the case of C(3)-methyl ether of 8α-estra-1,3,5(10)-trien-17-one (Bull. Soc. Chim. Fr. 1967, 561), an in-depth typical description is given. After the ketone is converted into a sulfonylhydrazone, in the simplest case by reaction with phenylsulfonyl hydrazide, the formation of the C(16)—C(17) olefin is carried out in a decomposition reaction (Z. Chem. 1970, 10, 221–2; Liebigs Ann. Chem. 1981, 1973–81), on which hypobromide is stored in a regio/stereocontrolled way. Reductive dehalogenation and removal of the protective group at C(3) produce the 16β-alcohol, which can be converted into the 16α-epimer according to known methods.
Another variant for the introduction of the hydroxyl group to C atom 16 exists in the hydroboration of the 16(17)-double bond with sterically exacting boranes. It is known of this reaction that it results in 16-oxygenated products (Indian J. Chem. 1971, 9, 287–8). Consequently, the reaction of 3-methoxyestra-1,3,5(10),16-tetraene and 3-methoxy-18α-homoestra-1,3,5(10),16-tetraene with 9-borabicyclo[3.3.1]nonane produces 16α-hydroxyestratrienes after oxidation with alkaline hydrogen peroxide. To a lesser extent, the epimeric 16β-hydroxy steroids are formed in this reaction. After the cleavage of the 3-methoxy group, estra-1,3,5(10)-3,16α-diols are obtained. By inversion of the configuration at C atom 16, e.g., by Mitsunobu reaction (Synthesis 1980, 1), the 16β-hydroxyestratrienes are in turn obtained.
The broad applicability of the synthesis method that is outlined above is demonstrated in additional examples, thus, for example, for 3-methoxy-7α-methylestra-1,3,5(10)-trien-17-one (Helv. Chim. Acta 1967, 281) or 1,3-dimethoxy-1,3,5(10)-trien-17-one (J. Org. Chem. 1967, 32, 4078).
The production of the central C(16)–C(17) olefinic intermediate stages is not limited to the arylsulfonylhydrazone method. If substituents on the steroid skeleton are not compatible with the basic reaction conditions of olefination, other processes, especially the conversion of the C(17) ketones into vinyl iodide (Tetrahedron 1988, 147) or enol triflates (Tetrahedron Letters 1984, 4821) and their subsequent reduction are suitable as alternatives.
If a synthesis pathway that runs through C(16)-keto derivatives, which then are converted into C(16)-alcohols or, by inversion, into C(16)a-alcohols, is selected, the possibilities for C(17)–→C(16)-ketotransposition are also selected. For a concrete example, refer to J. Chem. Soc. Perk. 1, 1976, 1350.
The introduction of fluorine atoms on carbon atoms 15 and 17 of the 16-hydroxyestratrienes according to the invention is possible by hydroboration of 15-fluoroestra-1,3,5(10),16-tetraenes or 17-fluoroestra-1,3,5(10),16-tetraenes with a sterically exacting borane and oxidation with alkaline hydrogen peroxide. The synthesis of 15-fluoroestra-1,3,5(10),16-tetraenes can be carried out from, for example, 15-hydroxyestra-1,3,5(10)-trien-17-ones. First, the secondary hydroxyl group must be substituted on carbon atom 15 by a fluorine atom. In this respect, for example, the 15α-hydroxyestrone that is accessible according to U.S. Pat. No. 3,375,174 is converted with known processes into 15β-fluoroestrone, by being reacted with diethylamino sulfur trifluoride or the corresponding 15α-mesylate being reacted with tetra-n-butylammonium fluoride (J. Chem. Res. (M) 1979, 4728–55). The thus accessible 15β-fluoroestra-1,3,5(10)-trien-17-ones are converted into tosyl hydrazones. The Bamford-Stevens reaction of the 15-fluorinated tosyl hydrazones produces the 15-fluoroestra-1,3,5(10),16-tetraenes that are required for the introduction of the 16-hydroxyl group. The 17-fluoroestra-1,3,5(10),16-tetraenes that are necessary for the synthesis of 17-fluorinated 16-hydroxyestratrienes are accessible according to established processes. Corresponding ketones can be converted into geminal difluorides by reaction with sulfur tetrafluoride (J. Org. Chem. 1971, 36, 818–20) or dialkylaminosulfur trifluorides, such as diethylaminosulfur trifluoride (U.S. Pat. No. 3,976,691). Hydrogen fluoride can be eliminated from these geminal difluorides by heating with aluminum oxide in an inert solvent according to U.S. Pat. No. 3,413,321, whereby fluoro-olefins are obtained. In addition, such fluoro-olefins can be obtained directly from ketones, if the ketones are reacted with diethylaminosulfur trifluoride in polar solvents with the addition of strong acids, e.g., fuming sulfuric acid (U.S. Pat. No. 4,212,815). The 17-fluoroestra-1,3,5(10),16-tetraen-3-ol that is described in U.S. Pat. No. 3,413,321 can be converted into a 17β-fluoroestra-1,3,5(10)-trien-3,16α-ol after the reaction with a sterically exacting borane and subsequent oxidation with alkaline hydrogen peroxide.
As a further modification, the introduction of double bonds may be useful. In addition to their pharmacological importance as selective estrogens in the context of this invention, these unsaturated derivatives represent valuable intermediate products for the synthesis of novel 16-hydroxyestra-1,3,5(10)-trienes. Below, the procedure for introducing a 9(11)-double bond is explained: A-ring-aromatic steroids are converted into the 9α-hydroxy steroids by dimethyl dioxiram; their dehydration results in estra-1,3,5(10),9(11)-tetraenes (Tetrahedron 1994, 50, 10709–20). By action of in-situ-produced dimethyl dioxiram on 18α-homoestra-1,3,5(10)-triene-3,16α-diyldiacetate, the corresponding 9α-hydroxy compound can be produced. The dehydration of this tertiary alcohol results in 18α-homoestra-1,3,5(10),9(11)-tetraene-3,16α-diyldiacetate. After saponification, 18α-homoestra-1,3,5(10),9(11)-tetraene-3,16α-diol is obtained.
The compounds of general formula I according to the invention are produced as described in the examples. Additional compounds of general formula I can be obtained by an analogous procedure using reagents that are homologous to the reagents that are described in the examples.
Etherification and/or esterification of free hydroxy groups is carried out according to methods that are common to one skilled in the art.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following preferred specific embodiments are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever.
In the foregoing and in the following examples, all temperatures are set forth uncorrected in degrees Celsius; and, unless otherwise indicated, all parts and percentages are by weight.
The entire disclosure of all applications, patents and publications, cited above, and of corresponding German application No. 199 06 159.9 filed Feb. 9, 1999, is hereby incorporated by reference.